Furyl, phenylene, and thienyl leukotriene B4 analogues

ABSTRACT

This invention relates to a compound of the formula: ##STR1## or a pharmaceutically acceptable salt thereof wherein X is oxygen, sulfur, or --CH═CH--; 
     wherein Z is OR 1  or --NR 4  R 5  ; 
     wherein R 1  is hydrogen, lower alkyl, or a pharmaceutically acceptable cation; 
     wherein R 2  is H, --CH 3  or --C 2  H 5  ; 
     wherein R 3  is OH, H or ═O; 
     wherein R 4  and R 5  may independently be hydrogen, or lower alkyl having 1-6 carbon atoms, or R 4  and R 5  may act together with N to form a cyclic amide of the formula: ##STR2## wherein n is an integer from 4-5; and m is an integer from 0-4. More particularly, this invention relates to compounds of the above formula which have utility as LTB 4  antagonists.

This application is a continuation-in-part of U.S. application Ser. No.130,355, filed 12/8/87, now abandoned.

BACKGROUND OF THE INVENTION

(a) Field of the Invention

The present invention relates to pharmaceutical agents (compounds) whichact as leukotriene B₄ (LTB₄) antagonists in mammals. The compounds ofthe present invention are useful in treating inflammatory conditions inmammals such as psoriasis, Crohn's disease, ulcerative colitis and thelike.

(b) Prior Art

LTB₄ (Formula I) is an arachidonic acid metabolite which is produced bythe 5-lipoxygenase pathway. Pharmacologically, LTB₄ is an importantmediator of inflammation in mammals. As a mediator of inflammation, LTB₄is known to induce chemotaxis, chemokinesis, aggregation, anddegranulation of leukocytes in vitro, and to induce accumulation ofpolymorphonuclear leukocytes, and increase vascular permeability andedema formation in vivo. ##STR3##

Particularly high levels of LTB₄ are detected in lesions in inflammatorydiseases such as rheumatoid or spondylarthritis, gout, psoriasis,ulcerative colitis, Chron's disease, and some respiratory diseases.

Accordingly, it is an object of this invention to produce compounds foruse as pharmaceutical agents which will exhibit LTB₄ antagonist activityin mammals.

A potential LTB₄ antagonist (Formula II), which is structurallydifferent from the compounds of the present invention, is disclosed inBiochem. and Biophys. Res. Comm., 138 540-546 (1986). ##STR4##

In this article, the authors also suggest that they have foundantagonistic activity in a series of unidentified unsaturated dihydroxyfatty acid derivatives which are to be the subject of a futurepublication.

Furber, et al., disclose the preparation of LTB₄ analogues of FormulasIII-V wherein phenyl or pyridyl ring provides the trans, trans doublebonds corresponding to C-8 and C-10 trans trans double bonds innaturally occurring LTB₄. J. Chem. Soc. Perkin Trans. I, 7 1573 (1987).##STR5##

The pharmacology of the biologically active leukotrienes is generallydiscussed in J. Clin. Invest. 73, 889-897 (1984).

SUMMARY OF THE INVENTION

This invention relates to a compound of the formula: ##STR6## or apharmaceutically acceptable salt thereof wherein X is oxygen, sulfur, or--CH═CH--;

wherein Z is OR¹ or --NR⁴ R⁵ ;

wherein R¹ is hydrogen, lower alkyl, or a pharmaceutically acceptablecation;

wherein R² is --H, 'CH₃ or --C₂ H₅ ;

wherein R³ is OH, H or ═O;

wherein R⁴ and R⁵ may independently be hydrogen, or lower alkyl having1-6 carbon atoms, or R⁴ and R⁵ may act together with N to form a cyclicamide of the formula: ##STR7## wherein n is an integer from 4-5; andwherein m is an integer from 0-4.

DETAILED DESCRIPTION

This invention encompasses compounds of Formula VI as previouslydescribed. A particularly preferred embodiment of the present inventionis encompassed by a compound of the formula: ##STR8## or apharmaceutically acceptable salt thereof, wherein Y is ##STR9## and

wherein R¹, R², R³, R⁴, R⁵, n, m, and Z are as previously defined forFormula VI.

The term "lower alkyl" as used to described R¹, R⁴, and R⁵ meansstraight or branched chain alkyls having 1-6 carbon atoms.

The term "pharmaceutically acceptable cations" as used to describe R¹refers to cations such as ammonium, sodium, potassium, lithium, calcium,magnesium, ferrous, zinc, copper, manganous, aluminum, ferric, manganic,ammonium, tetraalkylammonium, and the like.

The term "pharmaceutically acceptable non-toxic addition salts" referseither to those base derived salts of any compound herein having acarboxylic acid function.

The base derived salts may be derived from pharmaceutically acceptablenontoxic inorganic or organic bases. Among the inorganic bases employedto produce said pharmaceutically acceptable salts are the hydroxidebases of the "pharmaceutically acceptable cations" disclosed above.

Among the organic bases employed to produce said pharmaceuticallyacceptable salts are the pharmaceutically acceptable non-toxic bases ofprimary, secondary, and tertiary amines. Especially preferred non-toxicbases are isopropylamine, diethylamine, ethanolamine, dicyclohexylamine,choline, and caffeine.

All the pharmaceutically acceptable non-toxic addition salts areprepared by conventional processes well known to those of ordinary skillin the art.

The compounds of this invention are generally prepared according to thescheme set out in Charts A-C, wherein two side chains are substitutedonto a dihalo aromatic moiety. By dihalo is meant dibromo, bromoiodo ordiiodo. In Charts A-C, the halo group is represented by the letter "Q".By aromatic moiety is meant phenyl, thienyl or furyl, corresponding to"X" in the aryl ring being --CH═CH--, --S, and --O-- respectively.

As disclosed in Chart A, the first chain can be added to the aromaticmoiety of formula (X) by performing a nucleophilic substitution of oneof the halogens "Q" such as via a reaction with 4-pentynoic acid, CuI,and Pd° in a basic solvent such as diethyl amine. In aromatic moietieshaving both a bromo and an iodo substituent, the substitution of thepentynoic acid occurs preferentially at the iodo bearing carbon atoms toproduce a 5-aryl-4-pentynoic acid species (XI).

Hydration of the triple bond, such as by concentrated sulfuric acid,produces a keto group at the C-5 position of the pentynoic acid, i.e., a5-aryl-5-oxopentanoic acid (XII). The carboxylic acid of XI is renderedneutral by esterification, such as by reaction with diazomethane, toproduce the corresponding methyl ester (XIII).

The second side chain is optionally 11 to 15 carbons long. Preferably,its length is selected to provide a 20 carbon chain lengthcorrespponding to the length of naturally occurring LTB₄ (I). Thus, whenthe first and second side chains on the aromatic moiety are ortho toeach other, the first side chain provides 5 carbon atoms whereas thearomatic moiety provides only 2 carbon atoms (having a 6-cis doublebond) to the chain. Accordingly, the remaining carbon atoms are providedby the second side chain which is preferably 13 carbons long, i.e. 20 -7=13 carbons. When the second side chain is 13 carbon atoms long, m ofFormula VI is 2. Analagously, when the first and second side chains arepara to each other, the aromatic moiety provides 4 carbon atoms to thechain and the second side chain is preferably 11 carbons long (m ofFormula VI is 0).

The second side chain may optionally have an unsaturated site so as toprovide unsaturation at the C-13 position in the backbone of the LTB₄analogues, which correspond to the C-13 cis-double bond in naturallyoccurring LTB₄. By "unsaturation" as used herein is meant an individualdouble or triple bond. Examples of unsaturated acyl chloridescorresponding to Formula XX of Chart B are given in Examples 30 and 31.

The addition of the second side chain to the aromatic moiety ispreferably accomplished using two segments. The first segment ispreferably short and will have two reactive terminus, both of which arepreferably nucleophilic. Substitution of this segment onto themonohalo-aromatic moiety XIII to produce XV is accomplished byperforming a nucleophilic substitution at the carbon bearing the secondbromo or iodo group, preferably with the nucleophile,trans-1,2-bis(tributylstannyl)ethylene XIV, in the presence of acatalyst, such as Pd°, in a nonpolar solvent, such as toluene, and inthe presence of heat. The nucleophile XIV is prepared according to theprocedure of Corey et al., J. Org. Chem., 40, 3788 (1975).

The tri-(n-butyl)stannyl terminus of XV is converted to thecorresponding trans vinyl bromide XVI by reaction with elemental brominein CCl₄ at low temperature, preferably around -20°C.

The second and longer segment of the second side chain is selectivelysubstituted and built up to provide the remainder of the 11-13 carbonside chain and has a reactive terminus for substitution of the vinylbromo group of XVI. For example, an acyl chloride having 7 to 9 carbonatoms is reacted at low temperature, preferably around 0°C, withbis-(trimethylsilyl)acetylene in the presence of AlCl₃ in a polaraprotic solvent, such as CH₂ Cl₂ to produce XXI. When m of Formula VI is2 and X in the aryl ring is --CH═CH--, the acyl chloride is nonanylchloride and the product XXI is 1-trimethylsilyl-1-undecyn-3-one(Example 5).

The keto group in XXI is reduced to the corresponding alcohol, XXII,preferably by reaction with a metal hydride, such as NaBH₄. Removal ofthe terminal trimethylsilyl group to produce the terminal alkyne XXIIIis accomplished by reaction of XXII with 1M tetra-n-butylammoniumfluoride in a polar solvent such as tetrahydrofuran.

The hydroxyl group of XXIII may optionally be protected as an ether,preferably by reaction with dihydropyran in the presence of a catalyticamount of an acid such as p-toluenesulfonic acid, producing thecorresponding tetrahydropyranyl (THP) ether XXIV.

Reaction of XXIV with a trialkylstannane, preferablytri-n-butylstannane, in the presence of a catalytic amount ofazoisobutyronitrile (AIBN) produces XXV, wherein a trans addition occursacross the triple bond with the bulky trialkylstannyl group adding atthe terminus. The resulting compound XXV is now suitable for reactionwith XVI in the presence of a Pd catalyst to form XXVI, wherein thetrans character about C-1 and C-3 on the second side chain are 100% and75% retained respectively.

Having formed the carbon skeleton for the products of this invention inXXVI, its THP ether may be cleaved by acid hydrolysis in methanol to thecorresponding hydroxyl group producing the hydroxyketoester XXVII. Thehydroxyketoester XXVII may be reduced to the correspondingdihydroxyester of this invention XXIX with a metal hydride, preferablyNaBH₄ is a protic solvent such as methanol at reduced temperature.

Alternatively, the keto group of XXVI may first be treated with a metalhydride as above to produce the corresponding hydroxy-THP ether of XVII.Acid hydrolysis of the hydroxy-THP-ether of XXVIII in methanol producednot only the hydrolyzed dihydroxy ester of this invention XXIX, but italso produced the methyl ether XXX corresponding to R² ═CH₃ to FormulasVI and VII. When the first and second side chains are ortho to oneanother, the reaction of XXVIII with a catalytic amount of acid inmethanol also produces a pair of benzofuran fused ring stereoisomerscorresponding to Example 14 herein.

The esters of this invention, such as XXVII, XXIX, and XXX, can beconverted into their corresponding carboxylate salts by basic hydrolysiswith an aqueous alcoholic solution of a base having a pharmaceuticallyacceptable cation. The method for formation of the base salts of acarboxylic acid is well known by those of ordinary skill in the art.

In yet an alternative scheme, which achieves the necessary diversity forZ of Formulas VI and VII, the ester of XIII is converted into itscorresponding amide XVII by reaction in the presence of NH₄ Cl with aprimary or secondary amine of the formula H-NR⁴ R⁵, wherein R⁴ and R⁵are independently hydrogen or lower alkyl of of 1-6 carbon atoms or R⁴,and R⁵ may act together with N to produce a 5 or 6 membered heterocyclicamine. When the heterocyclic amine is pyrrolidine and X in the aryl ringis --CH═CH--, the amide corresponds to Example 20 herein.

Thereafter, the amide of XVII is treated as the esters of formulasXIII-XXIX to produce the amides of the present invention.

The biological activity possessed by the compounds of this invention wasindicated by positive results to the "LTB₄ Receptor Binding Assay" andthe "Human Neutrophil Degranulation Assay".

Preparation of Human Neutrophilis

For use in both the "LTB₄ receptor Binding Assay" and the "humanNeutrophil Degranulation Assay", neutrophils were purified from venousblood of normal human donors using standard techniques of dextransedimentaion, centrifugation on Histopaque² (density solution) andhypotonic lysis of erythrocytes (Boyum, A., Isolation of Leukocytes FromHuman Blood: Further Observations. Scand. J. Lab. Clin. Inves. 21(Suppl. 97): 31, 1968). The purity of isolated neutrophilis was ≧95%.

LTB₄ Receptor Binding Assay

Neutrophils (4-6×10⁶) in 1ml of Hanks' balanced salt solution containing10mM Hepes Buffer (HBSS), pH 7.4 and 30 μM nordihydroguaiaretic acidwere incubated with 0.6nM (³ H) LTB₄ in the presence or absence of testcompounds. The incubation was carried out at 0°C. for 45 minutes andterminated by adding 5ml of ice-cold HBSS followed by rapid filtrationof incubation mixture under vacuum through GF/C glass fiber filters. Thefilters were further washed with 10ml HBSS and their radioactivitydetermined. Specific binding was defined as the difference between totalbinding and nonspecific binding which was not displaced by 10⁻ 7Munlabeled LTB₄.

The inhibition of specific binding was determined for representativecompounds of this invention, and the corresponding IC₅₀ valuescalculated (Table 1). An IC₅₀ is the concentration of the compound ofinterest which will inhibit the binding of LTB₄ by 50% of the LTB₄receptors. For example, for the compound of Example 31, the IC₅₀ wasdetermined to be approximately 6.3μM.

Human Neutrophil Degranulation Assay

LTB₄ induced neutrophil degranulation was determined by measuring therelease of myeloperoxidase activity into the incubation medium.Neturophils (3 ×10⁶) in 1ml HBSS solution were preincubated withcytochalasin B(5μg) at 37°C. for 5 minutes, followed by preincubationwith test compounds for 7 minutes. Neutrophils were then incubated for 2to 20 minutes with either LTB₄ (5 ×10⁻ 8M) or the chemotatic peptidef-met-leu-phe (5 ×10⁻ 6M) to induce degranulation. Following incubation,samples were centrifuged and myeloperoxidase was extracted from the cellpellets by sonication in phoshpate buffer containing 0.4% Triton X-100.Triton X-100 was also added to the supernatents to a concentration of0.4%. The supernatants and the pellet extracts were then assayedspectrophotometrically for myeloperoxide activity by determining therate of decomposition of H₂ O₂ withh o-dianisidine as hydrogen donor asdescribed by Renlund, D. G., MacFarlane, J. L., Christensen, R. D.,Lynch, R. E., and Rothstein, G., A Quantitative And Sensitive Method ForMeasurement Of Myeloperoxidase, Clinical Research 28:75A, 1980).Myeloperoxidase activity released into the supernatant was expressed asthe percent of the average total activity (pellet plus supernatant).

The inhibition of LTB₄ induced neutrophil degranulation was determinedfor representative compounds of this invention and their correspondingIC₅₀ values were calculated (Table 1). The concentration of a compoundwhich inhibited LTB₄ induced neutrophil degranulation by 50% wasdetermined to be its IC₅₀ value.

By virtue of their activity as LTB₄ antagonists, the compounds ofFormula I are useful in treating inflammatory conditions in mammals suchas psoriasis, Crohn's disease, ulcerative colitis and the like.Similarly, the compounds of Formula I can be used in preventingrecurring inflammatory attacks. A physician or veterinarian of ordinaryskill can readily determine whether a subject exhibits the inflammatorycondition. The preferred utility relates to treatment of ulcerativecolitis.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules, softgels, pills, powders, granules,elixirs, or syrups.

The compounds may also be administered intravascularly,intraperitoneally, subcutaneously, intramuscularly, or topically usingforms known to the pharmaceutical art. Moreover, they may beadministered rectally or vaginally, in such forms as suppositories orbougies. In general, the preferred form of administration is oral. Forthe orally administered pharmaceutical compositions and methods of thepresent invention, the foregoing active ingredients will typically beadministered in admixture with suitable pharmaceutical diluents,excipients, or carriers (collectively referred to herein as "carrier"materials) suitably selected with respect to the intended form ofadministration, that is, oral tablets, capsules, softgels, elixirs,syrups, drops, and the like, and consistent with conventionalpharmaecutical practices.

For example, for oral administration in the form of tablets or capsules,a therapeutically effective amount of one or more compounds of thepresent invention may be combined with any oral non-toxicpharmaceutically acceptable inert carrier such as lactose, starch,sucrose, cellulose, magnesium stearate, dicalcium phosphate, calciumsulfate mannitol, and the like, or various combinations thereof. Fororal administration in liquid forms, such as in softgelts, elixirs,syrups, drops and the like, a therapeutically effective amount of theactive drug components may be combined with any oral non-toxicpharmaceutically acceptable inert carrier such as water, saline,ethanol, polyethylene, glycol, propylene glycol, corn oil, cottonseedoil, peanut oil, sesame oil, benzyl alcohol, various buffers, and thelike, or various combinations thereof. Moreover, when desired ornecessary, suitable binders, lubricants, disintegrating agents, andcoloring agents can also be incorporated in the mixture. Suitablebinders include starch, gelatin, natural sugars, corn sweeteners,natural and synthetic gums such as acacia, sodium alginate,carboxymethylcellulose, polyethylene glycol, and waxes, or combinationsthereof. Lubricants for use in these dosage forms include boric acid,sodium benzoate, sodium acetate, sodium chloride, and the like, orcombinations thereof. Disintegrators include, without limitation,starch, methylcellulose, agar, bentonite, guar gum, and the like, orcombinations thereof. Sweetening and flavoring agents and preservativescan also be included where appropriate.

For intravascular, intraperitoneal, subcutaneous, or intramuscularadministration, one or more compounds of the present invention may becombined with a suitable carrier such as water, saline, aqueousdextrose, and the like. For topical administration, such as forpsoriasis, therapeutically effective amounts of one or more compounds ofthe present invention can be combined with pharmaceutically acceptablecreams, oils, waxes, gels and the like. Regardless of the route ofadministration selected, the compounds of the present invention areformulated into pharmaceutically acceptable dosage forms by conventionalmethods known to those skilled in the art. The compounds may also beformulated using pharmacologically acceptable base addition salts.Moreover, the compounds or their salts may be used in a suitablehydrated form.

Regardless of the route of administration selected, a non-toxic buttherapeutically effective quantity of one or more compounds of thisinvention is employed in any treatment. The dosage regimen forpreventing or treating inflammatory conditions with the compounds ofthis invention is selected in accordance with a variety of factors,including the type, age, weight, sex, and medical condition of thepatient, the severity of the inflammatory condition, the route ofadministration, and the particular compound employed in the treatment. Aphysician or veterinarian of ordinary skill can readily determine andprescribe the effective amount of the drug required to prevent or arrestthe progress of the condition. In so proceeding, the physician orveterinarian could employe relatively low doses at first andsubsequently increase the dose until a maximum response is obtained.Daily dosages of the compounds of the invention are ordinarily in therange of about 1.0mg/kg up to about 21.0 mg/kg, (preferably in the rangeof about 2.0 to 14.0 mg/kg (orally)).

The following examples illustrate the methods used to prepare thecompounds of this invention. These examples are given by way ofillustration only and in no way should be construed as limiting theinvention in spirit or in scope, as many modifications in materials andmethods will be apparent from this disclosure to those skilled in theart.

In the following examples, and throughout this application, a wavy linedefines a substituent as an asymmetric carbon having R or Sstereochemistry. ##STR10##

                                      TABLE 1                                     __________________________________________________________________________    Biological Activity For Representative Compounds Of The Invention                                               Inhibition of      Inhibition of                                                                 LTB.sub.4                                                  Receptor Binding                                                                       Boyden Chamber                                                                          Induced Neutrophil       Compound                          of LTB.sub.4                                                                           Inhibition at 10.sup.-5                                                                 Degranulation            (Example No.)                                                                         Structure                 IC.sub.50 (uM)                                                                         (as Antagonist)                                                                         IC.sub.50                __________________________________________________________________________                                                         (uM)                                                       3.0      8%        1.0                               ##STR11##                4.1      30        1.8                               ##STR12##                6.3      33        5.2                      __________________________________________________________________________

DESCRIPTION OF THE PREFERRED EMBODIMENT Example 15-(2-bromophenyl)-4-pentynoic acid ##STR13##

To 10 ml of diethylamine was added with stirring 0.5 g (5.1 mmol) of4-pentynoic acid, 1.4g (5 mmol) of 1-bromo-2-iodobenzene, and 60mg (0.05mmol) of tetrakis(triphenylphosphine)palladium(O) The slurry wasdegassed with argon and 0.19g (1.0 mmol) of CuI was added. The reactionmixture was stirred for 2 hr. at room temperature and then poured intoapproximately 100ml of a 10% HCl solution. The resulting precipitate wasfiltered, washed with water and dried. The solid was taken up in hotCHCl₃ and filtered to remove insoluble salts. After evaporation of thesolvent, the resulting orange solid was recrystallized from achloroform-hexane mixture to produce a tan solid, m.p. 87-91°C.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.Acetone-d.sub.6 (300 MHZ):                  ______________________________________                                        7.62(dd, 1H); 7.48(dd, 1H); 7.35(dt, 1H);                                     7.25(dt, 1H); 2.75(m, 2H); 2.65(m, 2H).                                       ______________________________________                                    

Example 2 2-bromo-δ-oxobenzenepentanoic acid ##STR14##

Into 20cc of concentrated H₂ SO₄ was dissolved 0.1g (0.4 mmol) of theproduct of Example 1 to give a brown solution. The solution was allowedto stand at room temperature for 10 minutes. Thereafter, the solutionwas cooled to 0°C. in an ice bath and ice was then added to it. Thesolution was then diluted with water and extracted twice with ethylacetate. The combined extracts were sequentially washed once each withwater and brine and then dried (MgSO₄). Removal of the solvent underreduced pressure produced a yellow oil which was used without furtherpurification.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        7.60(d, 1H); 7.4-7.2(m, 3H); 3.0(t, 2H); 2.5(t, 2H); 2.05(p,                  ______________________________________                                        2H).                                                                      

Example 3 methyl 2-bromo-δ-oxobenzenepentanoate ##STR15##

To 0.54g (2.0 mmol) of the product of Example 2 dissolved in ether wasadded an ethereal solution of excess diazomethane at 0°C. to produce a97% yield of the ester as a yellow oil. The ester was used withoutfurther purification.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        7.60(d, 1H); 7.40-7.25(m, 3H); 3.68(s, 3H); 2.99(t, 2H);                      2.45(t, 2H); 2.06(p, 2H).                                                     ______________________________________                                    

Example 4 methyl 2-(2-bromo-E-ethenyl)-δ-oxobenzenepentanoate ##STR16##

To 10ml of toluene was added 6.0g (9.9 mol) oftrans-1,2-bis(tri-n-butylstannyl)ethylene, which was prepared accordingto the procedure of Corey, et al., J. Org. Chem., 40, 3788 (1975), and0.5g (1.8 mmol) of the product of Example 3. To the solution was thenadded 0.040g (.035 mmol) of 2 mole%tetrakis(triphenylphosphine)palladium(O) and the solution was degassedwith argon. The reaction mixture was heated under argon for 1 hour at120°C. (oil bath). Thereafter, the reaction mixture was cooled to -20°C.To the reaction mixture was added dropwise with stirring, a solution of1.5ml (29.1 mmol) of Br₂ in 30ml of CCl₄ until thin layer chromatographyof the reaction mixture indicated that all of the product of Example 3was consumed. The volatile components were removed in vacuo. The residuewas flash chromatographed on a silica gel column. Sequential elutionwith hexane, 5% diethyl ether in hexane, and 10% diethyl ether in hexaneproduced 0.48g of the titled product. The product was triturated withcold hexame to give a white solid, m.p. 52-55°C.

Analysis for C₁₄ H₁₅ O₃ Br (MW =310.9): Calcd.: C, 54.04; H, 4.89; Br,25.68; Found: C, 53.59; H, 4.86; Br, 25.25.

Example ##STR17##

1-(trimethylsilyl)-1-undecyn-3-one

To 500ml of CH₂ Cl₂ was added 53ml (294 mmol) of nonanoyl chloride and50g (293.4 mmol) of bis(trimethylsilyl) acetylene. The reaction mixturewas cooled in an ice bath and 40g (300 mmol) of AlCl₃ was addedportionwise with stirring over 1/2 hour. After stirring for anadditional hour, the reaction mixture was quenched with ice. Water wasadded to the reaction mixture and it was extracted 3x with 200mlaliquots of diethyl ether. The combined extracts were washed 2x with50ml aliquots of saturated NaHCO₃, 1 x with brine, and then dried(MgSO₄). The solvent was removed in vacuo to give a brown oil which wasused without further purification.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        2.45(t, 2H); 1.55(m, 2H); 1.20(br s, 10H); 0.80(t, 3H); 0.15(s,               ______________________________________                                        9H).                                                                      

Example 1-(trimethylsilyl)-1-undecyn-3-ol ##STR18##

To 200ml of methanol was added 10g (41.93 mmol) of the product ofExample 5. The reaction mixture was cooled to 0°C. and 0.53g (14 mmol)of NaBH₄ was added portionwise over 5 minutes. After an additional 15minutes, the reaction was quenched with acetone and the solvent removedunder reduced pressure. The residue was partitioned between water anddiethyl ether. The aqueous layer was extracted one additional time withdiethyl ether and the combined organic extracts were washed 1x withbrine and then dried (MgSO₄). Thin layer chromatography indicated thecrude product to contain both the titled product and its unsilylatedanalogue. This was used in the next step without further purification.

    ______________________________________                                        Mixture:                                                                      .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        4.38(m, 1H); 2.48(d, 1H); 2.03(br.d, 1H); 1.95(br.d, 1H);                     1.72(m, 2H); 1.45(m, 2H); 1.28(m, 10H); 0.87(t, 3H); 0.19(s,                  ______________________________________                                        9H).                                                                      

Example 7 1-undecyn-3-ol ##STR19##

To 8.65g of the crude product from Example 6 was added 40ml of 1M (n-C₄H₉)₄ NF in tetrahydrofuran (THF). The reaction mixture became warm andstirring was continued at room temperature for 1/2 hour. Thereafter, thereaction mixture was poured into brine and extracted 2x with diethylether. The combined ether extracts were washed 2x with brine and thendried (MgSO₄). Removal of the solvent produced a brown oil. The oil wasflash chromatographed on a silica gel column. Gradient elution from 10%diethyl ether in petroleum ether to 20% diethyl ether in petroleum etherproduced 6.81g of the titled product as a yellow oil.

Analysis for C₁₁ H₂₀ O (MW =168.0): Calcd.: C, 78.51; H, 11.78; Found:C, 78.02; H, 12.43.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        4.38(dt, 1H); 2.45(dd, 1H); 2.04(br d, 1H); 1.7(m, 2H);                       1.45(m, 2H); 1.3(br. s, 10H); 0.88(t, 3H).                                    ______________________________________                                    

Example 8 2-[(1-ethynylnonyl)oxy]tetrahydro-2H-pyran ##STR20##

To 100ml of CH₂ Cl₂ was added 6.81g (40.5 mmol) of the product ofExample 8, 11ml (120 mmol) of dihydropyran, and 100mg ofp-toluenesulfonic acid. After 6 hours at room temperature, the reactionmixture still contained primarily starting material. The reactionmixture was stripped of all volatile materials and recharged with 10mlof dihydropyran. After stirring overnight, the reaction mixture washeated for 6 hr. at 80°C. Although thin layer chromatography indicatedthat some starting material was still present, the reaction mixture wascooled and diluted with diethyl ether. The diluted reaction mixture waswashed 1x with saturated NaHCO₃ and then dried (K₂ CO₃). The solvent wasstripped in vacuo and the residue chromatographed on a silica gelcolumn. Elution of the column with 10% diethyl ether in petroleum etheryielded 3.12g of the titled product.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        4.98, 4.75(t, 1H); 4.4, 4.28(dt, 1H); 4.02, 3.80(m, 1H); 3.54(m, 1H);         2.44, 2.38(d, 1H); 2.0,-1.4(m, 8H); 1.3(br. s, 12H); 0.89(t,                  ______________________________________                                        3H).                                                                      

Example 9tetrahydro-2-[[1-[2-(tributylstannyl)-E-ethenyl]nonyl]oxy]-2H-pyran##STR21##

To 0.05g (0.19 mmol) of the titled product of Example 8 is addd 0.6ml(0.22mmol) of tri-n-butyltin hydride, and 20mg of azoisobutyronitrile(AIBN). The reaction mixture was heated at 110°C for 3 hours, whereuponthin layer chromatography indicated that the reaction was complete,producing the titled product. The product was used without furtherpurification.

Example 10 methylδ-oxo-2-[5-[(tetrahydro-2H-pyran-2-yl)oxyl]-1E,3E-tridecadienyl]benzenepentanoate##STR22##

To 1ml of toluene was added 0.1g (0.35 mol) of the product of Example 4,0.11g (0.38 mmol) of the product of Example 9, and 5.0mg oftetrakis(triphenylphosphine)palladium(O). The solution was degassed withargon and then heated at reflux under argon for approximately 5 hours.The reaction mixture was then cooled to room temperature and flashchromatographed. Gradient elution with hexane, 1% diethyl ether inhexane, 5% diethyl ether in hexane, and 10% diethyl ether in hexaneproduced 0.90mg (0.19 mmol) of the titled product.

    ______________________________________                                        .sup.1 H NMR  .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                              ______________________________________                                        7.58(m, 2H); 7.43(m, 1H); 7.30(m, 1H); 6.98(dd, 1H); 6.68(m, 1H);             6.35(m, 1H); 5.86(dd) + 5.63(dd)(1H); 4.71(t) + 4.66(t)(1H);                  4.15(m, 1H); 3.90(m, 1H); 3.66(s, 3H); 3.49(m, 1H); 2.95(dt, 2H);             2.42(t, 2H); 2.05(m, 2H); 1.9-1.2(complex m, 20H); 0.85(t,                    ______________________________________                                        3H).                                                                      

Example 11 methyl2-(5-hydroxy-1E,3E,-tridecandienyl)-δ-oxobenzenpentanoate ##STR23##

To 1ml of a 3:1:1 solution of acetic acid, water, and tetrahydrofuran(THF) was added 20mg (0.041 mmol) of the titled product of Example 10and the reaction mixture was allowed to stir 16 hr. After this time,some insoluble oil was still present and approximately 50μl of THF wasadded to the reaction mixture and it was stirred for an additional 2hours. The volatile components were removed in vacuo and the residue wasflash chromatographed. Elution with 1:1 diethylether-hexane produced10mg of the desired product.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        7.58(m, 2H); 7.43(t, 1H); 7.3(m, 1H); 6.99(d, 1H); 6.65(dd, 1H);              6.42(dd, 1H); 5.85(dd, 1H); 4.20(m, 1H); 3.68(s, 3H); 2.95(t, 2H);            2.42(t, 2H); 2.05(p, 2H); 1.55(m, 2H); 1.25(br. s, 12H); 0.88(t,              ______________________________________                                        3H).                                                                      

Example 12 methylδ-hydroxy-2-[5-[(tetrahydro-2H-pyran-2-yl)oxy]-1E,3E-tridecadienyl]benzenepentanoate##STR24##

To 3 ml of methanol was added 0.1g (0.21 mmol) of the titled product ofExample 10. The reaction mixture was cooled to 0°C. and 3mg of NaBH₄ wasadded. After 30 minutes, the reaction was complete. The reaction mixturewas quenched with acetone and the volatile components were removed invacuo. The residue was partitioned between diethyl ether (ether) andwater. The organic layer was separated and the aqueous layer wasextracted once more with ether and the combined extracts were washedwith brine and dried (K₂ CO₃). Removal of the solvent produced 0.11g ofa pale yellow oil. The product of this reaction was used without furtherpurification.

    ______________________________________                                        .sup.1 H NMR  .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                              ______________________________________                                        7.48(m, 2H); 7.23(m, 2H); 6.83(dd, 1H); 6.65(m, 1H); 6.39(m, 1H);             5.86(dd) + 5.62(dd)(1H); 5.02(br.s., 1H); 4.70(m, 1H); 4.15(m, 1H);           3.89(m, 1H); 3.64(s, 3H); 3.49(m, 1H); 2.33(t, 2H); 2.10(m, 1H);              1.90-1.15(complex m, 24H); 0.85(t, 3H).                                       ______________________________________                                    

Example 13 methylδ-hydroxy-2-(5-hydroxy-1E,3E-tridecadienyl)benzenepentanoate ##STR25##

To 3ml of methanol is added 0.1g (0.21 mmol) of the titled product ofExample 12 and 10mg of p-toluenesulfonic acid. The reaction mixture isheated to 55°C. for 3 hours. The solvent was removed under reducedpressure and the residue was flash chromatographed on silica gel column.Elution with 2:1 diethyl ether hexane produced 3 bands. The third bandcontained 0.30g of the titled products which was collected as fractions8-18.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        7.48(m, 2H); 7.25(m, 2H); 6.86(d, 1H); 6.65(dd, 1H); 6.43(dd, 1H);            5.84(dd, 1H); 5.02(t, 1H); 3.65(s, 3H); 3.63(m, 1H); 2.35(t, 2H);             2.0-1.2(complex, 20H); 0.88(t, 3H).                                           ______________________________________                                    

Example 14 methyl3-(1E,3E-dodecadienyl)-1,3-dihydro-1-isobenzofuranbutanoate ##STR26##

The first band which was eluted from the column in Example 13 wasfurther purified on high pressure liquid chromatography (HPLC).Fractions 20-23 from the HPLC produced 0.010g of a 5:1 mixture ofisomers A and B. Fractions 24-29 from the HPLC produced 0.0044g of pureisomer B.

    ______________________________________                                        Isomer A                                                                      .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        7.26(m, 2H); 7.13(m, 2H); 6.33(dd, 1H); 6.03(dd, 1H); 5.78(m, 1H);            15.6(m, 2H); 5.33(m, 1H); 3.66(s, 3H); 2.38(t, 2H); 2.07(m, 2H);              1.78(m, 4H); 1.38(m, 2H); 1.28(br. s, 10H); 0.89(t, 3H).                      ______________________________________                                        Isomer B                                                                      .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        7.27(m, 2H); 7.14(m, 2H); 6.36(dd, 1H); 6.06(dd, 1H); 5.78(m, 1H);            5.55(m, 2H); 5.20(m, 1H); 3.66(s, 3H); 2.39(t, 2H); 2.09(q, 2H);              1.85(m, 4H); 1.39(m, 2H); 1.28(br. s, 10H); 0.89(t, 3H).                      ______________________________________                                    

Example 15 methylδ-hydroxy-2-(5-methoxy-1E,3E-tridecadienyl)benzenepentanoate ##STR27##

The titled compound was prepared and worked up according to theprocedure of Example 13. Flash chromatography of the reaction mixtureproduced 3 bands when the column was eluted with 2:1 diethylether-hexane. The second band, which was eluted as fractions 4-6,produced 0.030g of the titled product upon evaporation of the solvent.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        7.49(m, 2H); 7.25(m, 2H); 6.87(d, 1H); 6.65(dd, 1H); 6.38(dd, 1H);            5.65(dd, 1H); 5.03(m, 1H); 3.66(s, 3H); 3.40(m, 1H); 3.30(s, 3H);             2.36(t, 2H); 2.03(d, 1H); 1.9-1.4(complex, 6H); 1.28(br. s., 12H);            0.88(t, 3H).                                                                  ______________________________________                                    

Example 16 δ-hydroxy-2-(5-hydroxy-1E,3E-tridecadienyl) benzenepentanoicacid, lithium salt ##STR28##

To 0.3ml of methanol was added 0.0065g (.0162 mmol) of the titledcompound from Example 13. The solution was cooled to 0°C. (ice bath) and0.1ml of H₂ O was added followed by 20μl of 1M LiOH (.02 mmol). Themixture was stirred as a slurry for 5 minutes and the ice bath wasremoved. Stirring was continued overnight. The reaction mixture was thenconcentrated with a stream of N₂ plus the last traces of solvent wereremoved at high vacuum to afford the title compound.

Example 17 3-(1E,3E-dodecadienyl)-1,3-dihydro-1-isobenzofuranbutanoicacid, lithium salt, isomer A ##STR29##

The titled compound was prepared by reacting 0.0047g of isomer (A)containing approximately 16% of Isomer B, the upper fraction of Example14, according to the procedure of Example 16, using 15μl of 1M LiOHinstead of 20μl of 1M LiOH.

This produced the lithium salt as a 5:1 mixture of Isomers A and B.

Example 18 3-(1E,3E-dodecadienyl)-1,3-dihydro-1-isobenzofuranbutanoicacid, lithium salt, isomer B ##STR30##

The titled compound was prepared by reacting 0.0016g of isomer B, thelower fraction of Example 14, according to the procedure of Example 16,using 6μl of 1M LiOH instead of 20μl of 1M LiOH.

Example 19 δ-hydroxy-2-(5-methoxy-1E,3E-tridecadienyl) benzenepentanoicacid, lithium salt ##STR31##

The titled compound was prepared by reacting 0.0041g of the product ofExample 15 according to the procedure of Example 16, using 11μl of 1MLiOH instead of 20μl of 1M LiOH.

Example 20 1-[5-(2-bromophenyl)-1,5-dioxopentyl]pyrrolidine ##STR32##

To 1ml of pyrrolidine is added with stirring 0.100g (0.35 mmol) of theproduct of Example 3, and 5mg of NH₄ Cl. The combined reagents werestirred in a sealed tube for 16 hours at room temperature. After thistime, an additional 1ml of pyrrolidine and 5mg of NH₄ Cl was added andthe reaction mixture was stirred an additional 16 hours. The solvent wasremoved under reduced pressure and the residue was flashchromatographed. Elution with diethyl ether produced 0.13g of the titledproduct, which was used without further purification.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        7.59(dd, 1H); 7.45-7.25(m, 3H); 3.44(m, 4H); 3.04(t, 2H);                     2.49(t, 2H); 2.06(p, 2H); 1.89(m, 4H).                                        ______________________________________                                    

Example 211-[5-[2-(2-bromo-E-ethenyl)phenyl]-1,5-dioxopentyl]pyrrolidine ##STR33##

To 1ml of toluene was added 0.13g (.40 mmol) of the titled product fromExample 20, 0.36g (.60 mmol) oftrans-1,2-bis-(tri-n-butylstannyl)ethylene, and 9mg (0.008 mmol) oftetrakis(triphenylphosphine)palladium(O). The solution was degassed withargon and heated at 120°C. for 1 hour. The reaction was cooled to -20°C.and treated with Br₂ in CCl₄ according to the procedure of Example 4.Upon evaporation of the volatile components in vacuo the reactionmixture produced a gummy yellow solid. The gummy solid was trituratedwith ether to produce 0.11g of a yellow solid, which was used withoutfurther purification.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        7.75-7.30(m, 5H); 6.63(d, 1H); 3.45(p, 4H); 3.03(t, 2H);                      2.35(t, 2H); 2.05(p, 2H); 1.90(m, 4H).                                        ______________________________________                                    

Example 22 1-(tributylstannyl)-1E-undecen-3-ol ##STR34##

To 0.07g (0.42 mmol) of the titled product of Example 7 is added 0.15g(0.5 mmol) of tri-n-butyltin hydride and 20mg of azoisobutyronitrile(AIBN). The reaction mixture was heated to 120°C. for 2 hours.Afterwards, it was cooled to room temperature and pumped at high vacuumovernight. The crude reaction mixture was then heated to 90°C. andmaintained at high vacuum for 2 additional hours. Upon cooling to roomtemperature, the crude product was used as is.

Example 231-[5-[2-(5-hydroxy-1E,3E-tridccadienyl)-phenyl]-1,5-dioxopentyl]pyrrolidine##STR35##

To 2ml of toluene is added all of the crude residue from Example 22,0.11g (0.31 mmol) of the product from Example 21, and 10mg oftetrakis(triphenylphosphine)palladium(O). The solution was degassed withargon, and then heated to reflux under argon for approximately 5 hours.Afterwards, the reaction mixture was cooled to room temperature andflash chromatographed. Gradient elution beginning with diethyl ether(ether) and going to 1:1 ether-ethyl acetate, produced the titledproduct. The product was used without purification.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        7.75-7.25(m, 4H); 7.0(d,1H); 6.65(dd, 1H); 6.40(dd, 1H);                      5.85(dd, 1H); 4.19(m, 1H); 3.41(m, 4H); 3.01(m, 2H); 2.38(t, 2H);             2.05(p, 2H); 1.90(m, 4H); 1.6(m, 2H); 1.30(br. m, 12H); 0.89(t,               ______________________________________                                        3H).                                                                      

Example 241-[5-hydroxy-5-[2-(5-hydroxy-1E,3E-tridecadienyl)phenyl]-1-oxopentyl]pyrrolidine##STR36##

The crude residue from Example 23 was taken up in 2ml of methanol andcooled to 0°C. 11mg (0.3 mmol) of NaBH₄ was added portionwise until thinlayer chromatography (TLC) of the reaction mixture showed no startingmaterial remaining. The solvent was removed under reduced pressure andthe residue was flash chromatographed using 1:1 diethyl ether/ethylacetate as the eluent. The later eluting fractions were collected,combined, and the solvent removed under reduced pressure. The residuewas again flash chromatographed. Elution with diethyl ether followed bytetrahydrofuran produced 0.01295g of the titled product.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        7.49(m, 2H); 7.24(m, 2H); 6.85(dd, 1H); 6.65(dd, 1H); 6.41(dd, 1H);           5.83(dq, 1H); 5.0(t, 1H); 4.19(q, 1H); 3.44(t, 2H); 3.38(t, 2H);              2.30(t, 2H); 2.0-1.6(m, 10H), 1.55(m, 2H);                                    1.30(br. s, 10H); 0.88(t, 3H).                                                ______________________________________                                    

Example 23 5-(5-iodo-2-thienyl]-4-pentynoic acid ##STR37##

To 75ml of diethylamine was added with stirring 3.76g of 4-pentynoicacid, 22g of 2,4-diiodothiophene, and 300mg oftetrakis(triphenylphosphine)palladium(o). The slurry was degassed withargon and 960mg of CuI was added. The slurry was maintained under argonand allowed to stir overnight, producing a dark brown solution.Thereafter, the solvent was removed under reduced pressure and 100ml of10% HCl was added to the residue. The residue was filtered and thenextracted 3x with ethyl acetate. The combined extracts were washed 1xwith water, dried over anhydrous MgSO₄, filtered, and stripped. Theresulting residue was flash chromatographed on a column of silica gel.Elution with a mixture of 30/70/2 parts ethyl acetate/hexane/acetic acidproduced 3.5 g of the titled product as a yellow solid.

Analysis for C₉ H₇ IO₂ S (MW =306.12): Calcd: C, 35.31; H, 2.31; I,41.46, Found: C, 35.44; H, 2.30; I, 41.37.

Example 26 methyl 5-iodo-δ-oxo-2-thiophenepentanoate ##STR38##

To 2.0g of the product from Example 25 was added 150ml of cooled (icebath) concentrated H₂ SO₄. The reaction mixture was stirred and shakenfor 10 minutes. Thereafter the reaction mixture was poured onto 800g ofcrushed ice. The resulting solid was filtered and washed 3x with H₂ O.The solid was dissolved in ethyl acetate, dried over anhydrous MgSO₄,filtered, and the solvent removed under reduced pressure. To theresulting green solid (ketoacid) was added a solution of etherealdiazomethane. The mixture was swirled until all the solid was dissolvedand the solution was allowed to stand overnight at room temperature. Thesolvent was then removed under reduced pressure and the residue flashchromatographed. Elution with 20/80 ethyl acetate/hexane produced 1.2gof the titled product as a white solid.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        7.34(d, 1H); 7.30(d, 1H); 3.69(s, 3H); 2.93(t, 2H);                           2.44(t, 2H); 2.05(m, 2H).                                                     ______________________________________                                    

Example 27 methyl 5-(2-bromo-E-ethenyl)-δ-oxo-2-thiphenepentanoate##STR39##

To 20ml of toluene was added 950mg of the titled product from Example26, and 3.4g of trans-1,2-bis-(tri-n-butylstannyl)ethylene. The flaskwas degassed with argon and 69mg of tetrakis-(triphenylphosphine)Pd(O)was added. The flask was sealed, heated to 120°C. (oil bath) for 20minutes, producing a dark brown solution containing thetrans-stannylvinylthiophene substitution product. The flask was thencooled to -25°C. (dry ice/isopropyl alcohol) and approximately 3ml of asolution containing 1.5ml Br₂ in 30ml CCl₄ was added dropwise withstirring until all the trans-vinylstannylthiophene was consumed. Thereaction mixture was worked up and chromatographed as in Example 4 toproduce 250mg of a pale yellow solid, which was a mixture of the titledproduct and the trans-iodovinylthiophene analogue.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        7.59(d, 1H); 7.18(d, 1H); 6.97(d, 1H); 6.86(d, 1H);                           3.69(s, 3H); 2.97(t, 2H); 2.45(t, 2H); 2.06(m, 2H).                           ______________________________________                                    

Example 28 methyl5-(5-hydroxy-1E,3E-tridecadienyl)-δ-oxo-2-thiophenepentanoate ##STR40##

The oil from Example 22 was taken up in 10ml of toluene. To thissolution was then added 200mg of the product mixture from Example 27 and15mg of tetrakis-(triphenylphosphine)palladium(O). The reaction mixturewas heated with stirring to 120°C. (oil bath) for 2 hours. Thereafter,the solvent was removed under reduced pressure and the residue was flashchromatographed on a silica gel column. Elution with 1:9 ethylacetate/hexane produced 65mg of the titled product as a liquid.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        7.58(d, 1H); 6.95(d, 1H); 6.79-6.57(m, 2H); 6.35(dd, 1H);                     5.93(dd, 1H); 4.21(m, 1H); 3.69(s, 3H); 2.94(t, 2H); 2.43(t, 2H);             (2.05(m, 2H); 1.58(m, 2H); 1.29(m, 2H); 0.93(t, 3H).                          ______________________________________                                    

Example 29 methylδ-hydroxy-5-(5-hydroxy-1E,3E-tridecadienyl)-2-thiophenepentanoate##STR41##

Into 3ml of methanol was dissolved 50mg of the titled product of Example28. The methanol solution was cooled to 0°C. (ice bath) and 5mg of NaBH₄was added. The reaction mixture was stirred for 1 hour at 0°C. and thenquenched with acetone. The solvent was removed from the quenced reactionmixture under reduced pressure. Water was added to the residue and itwas extracted 3x with ethyl acetate. The combined extracts were driedMgSO₄, filtered, and the solvent removed under reduced pressure. Theoily residue was chromatographed on a silica gel column. Elution with3:7 ethyl acetate:hexane produced 35mg of the titled product as a lightyellow oil.

Analysis for C₂₃ H₃₆ O₄ S (MW =408.65): Calcd.: C, 67.60; H, 8.88;Found: C, 67.24; H, 9.02.

    ______________________________________                                        .sup.1 H NMR δ .sub.TMS.sup.CDCl.sub.3 (300 MHZ):                       ______________________________________                                        6.80(dd, 2H); 6.65-6.45(m, 2H); 6.28(dd, 1H); 5.76(dd, 1H);                   4.85(m, 1H); 4.17(m, 1H); 3.67(s, 3H); 2.37(t, 2H); 1.94-1.62(m, 4H);         1.56(m, 2H); 1.42-1.1(m, 12H); 0.88(t, 3H).                                   ______________________________________                                    

Example 30 3-decynoyl chloride ##STR42##

To 6.8g (70 mmol) of 3-butynoic acid dissolved in 150ml of 1:1tetrahydrofuran (THF):hexamethyl phosphoric triamide (HMPA) and cooledto -20°C. is added via syringe a solution of n-butyl lithium in hexane(1.6N, 2 equiv). The mixture was allowed to warm to 0°C. The mixture isstirred for 30 minutes at this temperature and then 150g (1.1 equiv) of1-iodohexane is added dropwise as a solution in 20ml of THF. The mixtureis allowed to warm to room temperature and then is partitioned betweenether and water. The aqueous layer is acidified with 3N H₂ SO₄ andextracted with ether. The combined organic extracts are washed withbrine and dried (Na₂ SO₄). Evaporation of the volatiles in vacuo andchromatography of the crude on silica gel (ethyl acetate/hexane/aceticacid; 10:90:0.1) affords 4.5g of pure 3-decynoic acid.

The 3-decynoic acid is converted to its corresponding acyl chloride byreaction with thionyl chloride.

Example 31 3-decenoyl chloride ##STR43##

To 4.5g (27 mmol) of 3-decynoic acid from Example 30 dissolved inmethanol in a Paar bottle is added 2mg of nickel boride as catalyst. Thebottle is flushed with hydrogen, sealed and pressurized with H₂ at 2pounds per square inch. The hydrogenation is allowed to proceed at roomtemperature for 2 hours. The methanol is stripped in vacuo and theresidue is partitioned between ethyl acetate and in HCl. The ethylacetate layer is separated, dried, (Na₂ SO₄) and is stripped to affordan almost quantitative yield of 3-decenoic acid.

The 3-decenoic acid was converted to its corresponding acyl chloride(3-decenoyl chloride) by reaction with thionyl chloride.

Example 32 5-(hydroxy-1E,3E-tridecadienyl)-δ-oxo-2-thiophene-pentanoicacid, lithium salt ##STR44##

To 0.3ml of methanol was added 3.2 mg (0.0078 mmol) of the titlecompound from Example 28. To this solution was added 0.1cc of waterfollowed by 7.8μl of 1M LiOH and the mixture was stirred at R.T.overnight. Thereafter, the reaction mixture was concentrated with astream of N₂ and the last trace of solvent was removed at high vacuum toafford the title compound.

Example 33δ-hydroxy-5-(5-hydroxy-1E,3E-tridecadienyl)-2-thiophenepentanoic acid,lithium salt ##STR45##

The title compound was prepared by reacting 4.0mg of the product ofExample 29 according to the procedure of Example 32 using 12μl of 1MLiOH instead of 7.8μl of 1M liOH.

Example 34 2-(5-hydroxy-1E,3E-tridecadienyl)-δ-oxobenzenepentanoic acid,lithium salt ##STR46##

To 0.3ml of methanol was added 2.36mg (0.0059 mmol) of the titlecompound from Example 11. To this solution was added 0.2ml of waterfollowed by 7.8μl of 1 M LiOH and the mixture was stirred at roomtemperature (R.T.) overnight. Thereafter, the reaction was worked up asin Example 32 to produce the title product.

What is claimed is:
 1. A compound of the formula: ##STR47## or apharmaceutically acceptable salt thereof wherein X is --CH═CH:wherein Zis OR¹ ; wherein R¹ is hydrogen, or a pharmaceutically acceptablecation; wherein R² is H, --CH₃ or --C₂ H₅ ; wherein R³ is OH, H or ═O;and m is an integer from 0-4.
 2. A compound according to claim 1 of theformula: ##STR48## or a pharmaceutically acceptable salt thereof,wherein Y is ##STR49## wherein Z is OR¹ ; wherein R¹ is hydrogen, or apharmaceutically acceptable cation;wherein R² is --CH₃ or --C₂ H₅ ;wherein R³ is OH, H or ═O; and wherein R⁴ and R⁵ may independently behydrogen, or lower alkyl having 1-6 carbon atoms, or R⁴ and R⁵ may acttogether with N to form a cyclic amide of the formula: ##STR50## m is aninteger from 0-4.
 3. A compound according to claim 2 of the formula:##STR51##
 4. A compound according to claim 2 of the formula: ##STR52##5. A compound according to claim 2 of the formula: ##STR53##
 6. Apharmaceutical composition comprising a therapeutically orprophylactically effective amount of a compound according to claim 1 ina pharmaceutically acceptable carrier.
 7. A pharmaceutical compositionaccording to claim 6 wherein said composition is in oral dosage form. 8.A method of treating inflammatory conditions in mammals comprisingadmistering to a patient in need of such treatment, a therapeuticallyeffective amount of pharmaceutical composition according to claim
 6. 9.A method of preventing an inflammatory attach in mammals comprisingadministering to a patient susceptible to such attach a prophylacticallyeffective amount of a compound according to claim 1 in apharmaceutically acceptable carrier.